GIP (gastric inhibitory polypeptide or glucose-dependent insulinotrophic polypeptide) is one of the gastrointestinal hormones, and is secreted from K-cells present in the small intestine during meal ingestion. It is known that GIP functions as a suppressor of gastric-acid secretion and suppressor of gastric motility (see Patent Literatures 1 to 3).
It is also known that GIP promotes secretion of insulin from pancreatic β-cells and accelerates glucose uptake into adipocytes in the presence of insulin. It is therefore considered that the functions of GIP contribute to obesity. In fact, it was reported that obesity is suppressed when GIP functions are inhibited (see Non-patent Literature 4).
Furthermore, it was reported that GIP contributes to insulin resistance (see Non-patent Literature 4). When insulin resistance develops, the effect of insulin on sugar uptake decreases. As a result, hyperinsulinemia occurs. It is said that hyperinsulinemia is a fundamental cause leading to development of various lifestyle diseases such as obesity. Thus, it is important to prevent or reduce insulin resistance also from the viewpoint of decreasing the risk of lifestyle diseases.
Hence, effects such as promotion of digestion, reduction of upset stomach, and prevention or reduction of obesity and insulin resistance can be expected if GIP can be effectively suppressed.
Previous studies show that 3-bromo-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol (BMPP) and pyrazolopyrimidine compounds are substances capable of inhibiting the functions of GIP. Furthermore, guar gum and the like are known as substances capable of suppressing postprandial secretion of GIP (see Patent Literatures 1 and 2, and Non-patent Literatures 5 to 10). However, these substances have not been found to be sufficient from the viewpoints of safety and efficacy.
Insulin is one of the peptide hormones secreted from pancreatic β-cells in the pancreas, and functions to decrease elevated blood glucose level and maintain it at a normal level. The main physiological effects of insulin include promotion of uptake of sugars, amino acids and the like, and promotion of protein synthesis in the muscle tissue; promotion of sugar uptake and utilization thereof, promotion of lipid synthesis, suppression of fat decomposition and burning, and promotion of protein synthesis in the adipose tissue; and the like.
Secretion of insulin is promoted mainly by glucose. When blood sugar level (blood glucose level) elevates owing to introduction of sugar into the body such as after a meal, insulin is secreted so as to decrease the elevated blood sugar level. As a result, the blood insulin level elevates. The secretion of insulin is therefore very important for preventing diabetes mellitus by keeping blood sugar level constant.
However, it is known that continuous secretion of insulin under hyperglycemic condition leads to insulin resistance in the skeletal muscles, liver and adipose tissue that are target organs of insulin. When insulin resistance occurs, a larger amount of insulin is secreted from the pancreas so as to compensate for insufficient blood sugar reduction effect. When such an excess secretion of insulin is repeated, the pancreas gets exhausted, and finally the ability of the pancreatic β-cells to secrete insulin declines, while the high insulin resistance in the target organs is maintained. The above functional deterioration of the regulatory mechanism of insulin in the body leads to constitutional predispositions susceptible to development of lifestyle diseases such as diabetes mellitus, and as a result, obesity, Type II diabetes mellitus (hypertension) and the like are apt to develop (see Non-patent Literature 11).
Until recently, it has been considered that the amount of insulin secreted into the blood varies with blood sugar level, i.e., amount of carbohydrates ingested. But, in recent years, it was newly reported that fat uptake, as well as carbohydrate uptake, is also correlated with the elevation of blood insulin level (see Patent Literature 3). According to Patent Literature 3, it was confirmed that ingestion of carbohydrate together with fat induces excessive secretion of insulin beyond the level induced by ingesting carbohydrates alone. Further, it was also ascertained that the excessive secretion of insulin due to such simultaneous ingestion of carbohydrate and fat is a factor highly correlated to obesity.
Meanwhile, it was reported that hyperglycemia and hyperlipidemia are independent, risk factors for cardiovascular events (Non-Patent Literatures 12 and 13). In addition, it was reported regarding hyperglycemia that fasting hyperglycemia has a low correlation with the probability of death caused by circulatory diseases, whereas blood sugar level has a high correlation with the probability of death caused by circulatory diseases in patients with hyperglycemia having a 2-hour value of 200 mg/dL or more in the glucose tolerance test (OGTT) (Non-Patent Literature 13). It was further reported that in the case where vascular endothelial cells are cultured in a hyperglycemic state, apoptosis of the cells occurs with higher frequency when exposed to an intermittent hyperglycemic condition than when exposed to a continuous hyperglycemic condition (Non-Patent Literature 14).
Further, as compared to healthy people, insulin secretion is lower in diabetes mellitus type 1 patients and insulin secretion in the early postprandial period is lower in diabetes mellitus type 2 patients. The postprandial blood sugar level of healthy people is regulated by insulin, and in general, does not rise above 7.8 mmol/L (140 mg/dL) in response to eating, and generally returns to the level before meal ingestion within 2 to 3 hours (Non-Patent Literatures 15 and 16). In contrast, in type 1 and type 2 diabetic patients with decreased insulin functions, postprandial hyperglycemia is observed with extremely high frequency. Further, postprandial hyperglycemia is a phenomenon which appears before clinically obvious diabetes mellitus with a progressive decrease in insulin function and the β cell activity (a decrease in insulin secretion). It is therefore believed that the prevention of postprandial hyperglycemia leads to the prevention of diabetes mellitus and arteriosclerosis.
From such standpoint, administration of α-glucosidase inhibitors which delay the digestion and absorption of carbohydrates in the small intestine, administration of sulfonium urea formulations which promote insulin secretion, rapid-acting insulin secretagogues and the like are performed in order to reduce postprandial hyperglycemia.
The α-glucosidase inhibitors, however, have problems in that the effect cannot be exerted unless the inhibitors are administered before intake of carbohydrates; the inhibitors do not affect the elevation of blood glucose level caused by intake of glucose which is a monosaccharide; and intestinal symptoms such as diarrhea and gas retention caused by abnormal fermentation of sugars in the colon occur. In addition, the sulfonium urea formulations cannot exert the effect unless the formulations are administered before intake of carbohydrates, and when the formulations are administered excessively, excessive secretion of insulin is induced, to thereby cause hypoglycemia, so that caution is required. Further, these synthetic medical formulations cannot be easily obtained because prescriptions are required. In addition, the formulations may cause various adverse effects, and for the use thereof, strict supervision and guidance by doctors are required.
A triglyceride is a kind of neutral fat, and most neutral fats contained in blood are triglycerides. It is known that hypertriglyceridemia and hyperlipidemia develop with continuance of a high triglyceride level in the blood. Hyperlipidemia is considered to be a cause of arteriosclerosis, and act as the initial trigger for inducing disorders such as cardiac disease and cerebral vascular disease.
In general, since changes in blood triglyceride level are strongly affected by diet, complete regulation of blood triglyceride level using only medicaments is said to be difficult. A stronger focus has therefore been placed on the quality of ingested dietary fat than on medical therapy. For example, lowering blood triglyceride level by eating highly-unsaturated fatty acids, such as linoleic acid and linolenic acid, has been recommended. But, since excessive consumption of the highly-unsaturated fatty acids induces production of overoxidized fatty acids in vivo, the possibility of inducing various lifestyle related diseases has been pointed out.
From the viewpoint of the above circumstances, there is a need to suppress elevation of blood triglyceride level by a safer means which does not induce adverse effects even if involving administration or consumption on a daily basis. Recent years, as substances which suppress elevation of blood triglyceride level safely and effectively, xanthane gum, propylene glycol alginate ester (see Patent literature 4), chitosan (see Patent literature 5) and a processed starch (see Patent literature 6) have been reported as fat absorption suppressors.
Due to their high water retaining ability, polyglutamic acids are widely used as moisturizing agents, absorbing agents and the like in the fields of foods, medical treatment, cosmetics and the like, and have attracted attention as highly safe biodegradable polymers. It was reported that polyglutamic acids have an effect of promoting calcium absorption through the small intestine and an effect of suppressing elevation of blood pressure (for example, see Patent Literatures 7 and 8). In addition, an agent for reducing blood sugar level using polyglutamic acids has been suggested for suppressing elevation of blood sugar level (see Patent Literature 9). Further, it was reported that polyglutamic acids have an effect of suppressing the absorption of neutral fat, and can be used for the treatment, reduction and suppression of development of hypertriglyceridemia (see Patent Literature 10).
But no pharmaceutical effects of specific salts of polyglutamic acids have been reported so far.